Risk Based Monitoring Overview at BMS
Transcript of Risk Based Monitoring Overview at BMS
Risk Based Monitoring Overview at BMS
Patricia Clerton – Central Monitor
« Clinical Data, Real Data, Open & Big Data »
7 Novembre 2016 Cité Universitaire
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• What is RBM at BMS ?
• Focus on CMN role
• Questions
Agenda
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• What is RBM at BMS ?
• Focus on CMN role
• Questions
Agenda
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TransCelerate was founded in 2012
by 10 Biopharmaceutical
organizations.
What or Who is TransCelerate?Vision:
To improve the health of people around the world by accelerating and simplifying the research and development of innovative new therapies.
Mission Statement:
To collaborate across the global biopharmaceutical R&D community to identify, prioritize, design and facilitate implementation of solutions designed to drive the efficient, effective and high quality delivery of new medicines.
Strategic Priorities:
TransCelerate assesses industry challenges and selects initiatives aligned with five strategic priorities:
Enable Harmonization of Clinical Trial
Processes
Improve the Site Investigator Experience
Facilitate Information Sharing
Enhance Sponsor Efficiencies
Improve the Patient Experience
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RBM - An adaptive approach to clinical trial monitoring that directs monitoring focus and activities to the evolving areas of greatest need which have the most potential to impact patient
safety and data quality.
“The validity of a clinical trial is as dependent on monitoring GCP and adherence to the protocol as it is to the identification of errors and inconsistencies in the data” [Applied Clinical Trials 2011]
Agencies
• 2011: FDA, EMA, and MHRA guidances encourage risk-based monitoring, including adoption of alternative monitoring methods todecrease the reliance on on-site monitoring and utilize available technologies; CITI endorses QbD approach to study monitoring
• 2015: ICH E6
BMS
• RSDV program is difficult to implement and focuses on efficiency not quality;
• Audit and inspection findings cite deficits related to protocol compliance and unrelated to SDV. How can we identify that data is invalid even if it matches the source?
Consensus
• Focusing all roles on the most critical data elements is more likely to ensure overall study quality than 100% SDV with frequent monitoring visits
• BMS joins TransCelerate in 2012 to share solution ideas
Dri
vers
for
cha
nge:
Why is Risk-Based Monitoring necessary?
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newnew
SeptemberTransCelerate
BioPharma Incorporated
1st North American BMS RBM Pilot
July•BMS Adapted RBM Process
guidance
November•1st BMS Global
Pilot Study
2015
Embed RBM
CMN Function officially created
ImplementationPhased
CMN support initiated
Pilot Phase
Full Implementation
RBM Key Events
February•Studies in full RBM
process
201420132012 2016
HeadCMN
Centralized Statistical Analysis
(CSA) OC studies
August•RBM Audit
January•Medidata & BMS partner
CMN Team
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Identification of Critical Data/Risk
Assessments
PROGRAM
Identification of Critical Data/Risk
Assessments
PROTOCOL
Risk Plans Monitoring Execution
Program Level RACT*
Risk-Based Monitoring
Protocol Level RACT*
Monitoring Plan
Data Review Plan
Quality Risk Indicators
Acronyms:*RACT = Risk Assessment Categorization Tool
RBM => Planning for and Managing Risks and Issues
The BMS RBM Methodology
On & Off-Site Monitoring
Central Monitoring
Ongoing Site Management
Focus on the most meaningful data
Customize monitoring to
the needs of the trial;
Adjust activities based on
findings/issues
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Program Level RACT
Risk Assessment and Categorization Tool (RACT)
Documentation of Critical Data & Processes
• Team alignment on “what matters” • Focused Risk Assessment
Consistent Approach to Assessment
• Each category** has a series of questions to identify risks
Impact , Probability & Detectability
• Determines the impact to the study if the risk becomes an issue• Determines the probability of the risk occurring• Determines the ability to detect if a risk is becoming an issue
Output
• Provides direction on where the most attention is needed for monitoring and mitigation
• Determines the Overall Risk Level (high, medium, or low) for monitoring activities
**Categories**
Protocol Level RACT
Program Level RACT
• Safety• Endpoints• IP• Technology• Operational
Experience
• Study Phase
• Pt. Population
• Endpoints
• Technology
• Data Collection & CRF Source
• Study Medication/IP
• Blinding
• Clinical Supply Chain
• Operational Complexity
• Geography
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Identify Critical Data and Critical Processes
Critical Data Critical Processes
Definition
• Support primary and key secondary objectives
• Are critical to subject safety & the ethical treatment of subjects
• Processes that are critical to the reliability of the study findings. This may include: Processes that support the collection of
critical data Processes related to ensuring subject
safety Compliance with ICH-GCP regulationsDocumentation of trial integrity
Process
• Critical Data will be Source Data Verified (SDV) (i.e. transcription checking)
• SDV will initially target a percentage of subjects based on RACT determined Overall Study Risk Score
• Critical Processes will be Source Data Reviewed (SDR)
• SDR will initially target a percentage of subjects based on RACT determined Overall Study Risk Score
Example(s)• AE/SAE data• Date of progression
• Laboratory tests (collection, shipment)• Disease progression determination (accuracy
of tumor assessment criteria)
Critical Data & Critical Processes
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Central Monitoring
Remote assessment of study-level Quality
Risk Indicators
Off-Site Monitoring
Remote assessment of site-level Issues, data,
site performance
On-Site Monitoring
Assessment of site quality via SDV, SDR, GCP assessment at the
investigational site
Data ManagementReview
Safety Review
StatisticalReview
Comprehensive approach to monitoring
Fit for purpose
RBM Monitoring Execution
Medical Review
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Focus monitoring on the most critical data and processes Share responsibility for subject safety, data quality Customize monitoring approach to each trial/site based on risk assessment Monitoring as a cross-functional responsibility Use of technology to monitor study conduct Adapt monitoring approach in response to findings Rely more on Off-site and Central Monitoring
Recommended RBM Core Principles
As of September 2016, RBM has been implemented in ~58 of ongoing/planned studies(~46% total studies)
By the end of 2016, RBM is expected to be implemented in ~70% of studies
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GCOS: Clinical
Operations Risk Managers
**New Role**
RCO: Monitoring Excellence
Leads (SMN)
GDSS: Central Monitors (CMN)
RCO: SMP Writers & Global Site Monitors
RCO: Global Site Managers
(STM)
GCOS: Protocol
Managers (PTM)
RCO: Clinical Data Quality
Managers (CDQM)
GDSS: Data Leads and
Protocol Data Managers
Successful RBM
Cross-Functional RBM Team
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• What is RBM at BMS ?
• Focus on CMN role
• Questions
Agenda
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USA-Based
• Protocol Manager
• Manager of Site Manager
• Protocol Data Manager
• R&D Learning & Development
• Statistical Programming
• Site Monitor
• Global Regulatory Safety and Biometrics
• Manager of Protocol Data Managers
UK-Based
Clinical Data Quality Manager
Japan-Based
Clinical Data Quality Manager
France-Based
Clinical Data Quality Manager
Argentina-Based
Clinical Data Quality Manager
Head of
Central Monitoring
Central Monitoring Team - Former roles
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Centralized monitoring is a remote evaluation of ongoing and/or cumulative data collected from trialsites, in a timely manner. Centralized monitoring processes provide additional monitoringcapabilities that can complement and reduce the extent and/or frequency of on-site monitoring bysuch methods as:
Routine review of submitted data. Identification of missing data, inconsistent data, data outliers or unexpected lack of variability
and protocol deviations that may be indicative of systematic or significant errors in datacollection and reporting at a site or across sites, or may be indicative of potential datamanipulation or data integrity problems.
Using statistical analyses to identify data trends such as the range and consistency of data withinand across sites.
Analyzing site characteristics and performance metrics. Selection of sites and/or processes for targeted on-site monitoring.
ICH Addendum 5.18.3 to ICH E6
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To provide a unique analysis of ongoing and/or cumulative data To assess risk across sites, countries and studies To allow for early issue detection and targeted intervention
Central Monitor Responsibilities
Remote assessment of Quality Risk Indicators (QRIs) Identify issues/emerging risks in study specific variables (trends/outliers/poor performing sites) Support risk mitigation and global monitoring of processes that align with BMS programs and
protocols
Purpose
Central Monitoring at BMS
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Process
Central Monitoring Process
Generate reports to assess QRIs and
study specific risks
Investigate clinical data and
operational metrics for outliers and trends
Assign/escalate issues
at site, country, or study level to the appropriate role
Assess resolution, follow-up, and
provide documentation
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Risk Indicator Summary Cards – Quality Risk Indicators
• Screen fail rate• Treatment discontinuation
rate• Significant protocol deviation
rate
• SAE rate• % PT W/SAE• AE rate• % PT W/AE• RELAE rate• % PT W/RELAE• % RELAE of all NSAE
• Number of incomplete pages• CRF completion timelines• Discrepancy rate• Discrepancy resolution timelines
• SAE reporting timelines
• Systolic BP• Diastolic BP• Heart Rate
• Counts of Issues by type at each site reported on Issues Management Tool
Site Quality Site Safety Site Performance
Rate of Repeats Site Issues
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• Variety of reports in multiple systems
• Manually run and analyzed
• System retrieved reports• System analysis for outliers /
trends / thresholds• Improved graphical interfaceFu
ture
Sta
te
Centralized Monitoring ToolsC
urre
ntSt
ate
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VV1
Study team input, as needed
Central Monitors align
on findings
Site Level IssuesclinSIGHT issues management: Site
Monitor (SMN)
The issue resolver works with the site
The CMN is not a site facing role
Study/Country Level Issues
Email, TC: PTM, PDM, hub designee
Study team devises a plan of action to
address with sites e.g. training, email,
newsletter
PMF toolkit issues & risks log
Team Updates
RBM Q&A Calls
Team Meetings (e.g., IPT)
Issue Escalation
Communication Flow
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R e g u l a t o r yS u p p o r t
A n a l y t i c s & V i s u a l i z a t i o n s
R i s k M i t i g a t i o n
Central Monitoring
I s s u e E s c a l a t i o n
Unique analysis of aggregate data and comparison of QRIs
Utilize analytics & visualizations for assessment of issues/risks at the study, program, country, and therapeutic level
Early identification of critical data issues
Document findings for tracking, targeted intervention and timely resolution
Support regulatory audits and Health Authority inspections
Assess for potential fraud and protocol compliance
Ensure data quality at the program, indication and/or TA level
Application of RACT, DRST and risk mitigation plans
Key Benefits of Central Monitoring
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Risk Based Monitoring is an Industry-Wide Change driven by Regulators
Risk Based Monitoring is a Cross-Functional Collaboration
Risk Based Monitoring is an adaptive process that involves the early identification and assessment of risks, implementation of risk mitigations,
and execution of holistic monitoring approaches
Risk Based Monitoring focuses on what is most importantin order to protect the rights and safety of human subjects and to ensure data
integrity and GCP compliance
RBM: Key Takeaways
ICH recent Addendum supports how RBM is being implemented acrossindustry
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Questions?
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